The principal investigator (PI) is an infectious disease clinician and epidemiologist with a career interest in the etiologic determinants of the emergence and dissemination of drug-resistant bacteria. The PI's experience in clinical infectious diseases, epidemiology, molecular epidemiology, and microbiology, provide a solid foundation for the proposed research plan and demonstrate a strong commitment to a career in academic medicine. The career development plan detailed in this proposal integrates these prior training experiences, while allowing the PI to develop new expertise using a murine model to assess parasite virulence. Prior work by the PI has demonstrated that HIV infection plays a pivotal role in the emergence of rifampin mono-resistant (RMR) tuberculosis (TB), an increasingly significant public health problem. The PI now hypothesizes the malabsorption of anti-tuberculous drugs and the ability of relatively avirulent strains to produce disease in HIV-infected patients are important determinants of the emergence of RMR TB. The relationship between HIV and acquired RMR TB will be further elucidated in a case-control and a molecular epidemiologic study in San Francisco. A prospective cohort study in Botswana will define the prevalence and significance of the malabsorption of anti-tuberculous drugs. A series of investigations utilizing molecular epidemiologic techniques and a murine model will determine the relationship between specific mutations conferring rifampin-resistance and strain virulence, and the prevalence of avirulent strain in HIV-infected patients. Ultimately, these investigations will facilitate the formulation of interventions for preventing and controlling RMR TB. The intellectual environment at UCSF and the strong tuberculosis research group which Dr. Hopewell has created in San Francisco afford the PI an ideal opportunity to pursue his career development plan. The close proximity to UC Berkeley, the California Department of Health Services, and Stanford University, allow the PI to maintain important collaborations and to access diverse educational opportunities at these institutions.